This application is a 371 of PCT/EP99/02457, filed Apr. 12, 1999.
The invention relates to compounds of the formula I 
in which
R1, R4 in each case independently of one another are xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by xe2x80x94COA, xe2x80x94COxe2x80x94[C(R6)2]nxe2x80x94Ar, xe2x80x94COOA, xe2x80x94OH or by a conventional amino protective group, NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2, xe2x80x94COxe2x80x94Nxe2x95x90C(NH2)2, 
R2, R3, R5 in each case independently of one another are H, A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, NHCOAr, NHSO2A, NHSO2Ar, COOR6, CON(R6)2, CONHAr, COR6, COAr, S(O)nA, S(O)nAr, xe2x80x94Oxe2x80x94[C(R6)2]mxe2x80x94COOR6, xe2x80x94[C(R6)2]pxe2x80x94COOR6, xe2x80x94Oxe2x80x94[C(R6)2]mxe2x80x94CON(R6)2, xe2x80x94[C(R6)2]pxe2x80x94CON(R6)2, xe2x80x94Oxe2x80x94[C(R6)2]mxe2x80x94CONHAr, or xe2x80x94[C(R6)2]pxe2x80x94CONHAr,
X is xe2x80x94[CR6)2]nxe2x80x94, xe2x80x94CR6xe2x95x90CR6xe2x80x94, xe2x80x94[C(R6)2]nxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94[C(R6)2]nxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94, xe2x80x94CONR6xe2x80x94 or xe2x80x94NR6COxe2x80x94,
R6 is H, A or benzyl,
A is alkyl having 1-20 C atoms, in which one or two CH2 groups can be replaced by O or S atoms or by xe2x80x94CR6xe2x95x90CR6xe2x80x94 groups and/or 1-7 H atoms can be replaced by F,
Ar is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, Arxe2x80x2, OR6, OArxe2x80x2, N(R6)2, NO2, CN, Hal, NHCOA, NHCCOArxe2x80x2, NHSO2A, NHSO2Arxe2x80x2, COOR6, CON(R6)2, CONHArxe2x80x2, COR6, COArxe2x80x2, S(O)nA or S(O)nArxe2x80x2,
Arxe2x80x2 is phenyl or naphthyl, which is unsubstituted or mono-, di- or trisubstituted by A, OR6, N(R6)2, NO2, CN, Hal, NHCOA, COOR6, CON(R6)2, COR6 or S(O)nA,
Hal is F, Cl, Br or I,
n is 0, 1 or 2,
m is 1 or 2,
p is 1 or 2,
and their salts.
The invention also relates to the hydrates and solvates of these compounds.
The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties together with good tolerability. In particular, they exhibit factor Xa-inhibiting properties and can therefore be employed for the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
Aromatic amidine derivatives having antithrombotic action are disclosed, for example, in EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic disorders are described, for example, in WO 97/08165. Aromatic heterocycles having factor Xa-inhibitory activity are disclosed, for example, in WO 96/10022.
The antithrombotic and anticoagulating effect of the compounds according to the invention is attributed to the inhibitory action against the activated clotting protease, known under the name factor Xa. Factor. Xa is one of the proteases which is involved in the complex process of blood clotting. Factor Xa catalyzes the conversion of prothrombin into thrombin, which for its part contributes to thrombus formation. Activation of thrombin can lead to the occurrence of thromboembolic disorders.
Inhibition of the factor Xa can thus prevent thrombin being formed.
The compounds of the formula I according to the invention and their salts intervene in the blood clotting process by inhibition of the factor Xa and thus inhibit the formation of thrombi.
The inhibition of the factor Xa by the compounds according to the invention and the measurement of the anticoagulatory and antithrombotic activity can be determined according to customary in vitro or in vivo methods. A suitable procedure is described, for example, by J. Hauptmann et al. in Thrombosis and Haeemostasis 63, 220-223 (1990).
The measurement of the addition of factor Xa can be carried out, for example, according to the method of T. Hara et al. in Thromb. Haemostas. 71, 314-319 (1994).
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, in particular for the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
The invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that
a) they are liberated from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent by
i) liberating an amidino group from its oxadiazole derivative by hydrogenolysis,
ii) replacing a conventional amino protective group by hydrogen by treating with a solvolysing or hydrogenolysing agent or liberating an amino group protected by a conventional protective group, or
b) in a compound of the formula I, converting one or more radical(s) Y, R1, R2, R3, R4 and/or R5 into one or more radical(s) R1, R2, R3, R4 and/or R5, by for example,
i) hydrolysing an ester group to a carboxyl group,
ii) converting a hydroxylated amidino group to an amidino group,
iii) reducing a nitro group,
iv) acylating an amino group, and/or
c) converting a base or an acid of the formula I into one of its salts.
For all radicals which occur a number of times such as, for example, R6, it applies that their meanings are independent of one another.
Hydrates are understood as meaning, for example, the hemi-, mono- or dihydrates and solvates are understood as meaning, for example, alcohol addition compounds such as, for example, with methanol or ethanol.
In the above formulae, A is alkyl, is linear or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 C atoms. A is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl.
A is furthermore, for example, trifluoromethyl, pentafluoroethyl, allyl or crotyl.
COR6 is acyl and is preferably formyl, acetyl, propionyl, furthermore also butyryl, pentanoyl or hexanoyl. COOR6 is preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or butoxycarbonyl.
Hal is preferably F, Cl or Br, but also I.
R2, R3 and R5 are, in each case independently of one another, preferably H, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, nitro, amino, methylamino, dimethylamino, ethylamino, diethylamino, acetamido, sulfonamido, methylsulfonamido, phenylsulfonamido, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxymethoxy, methoxycarbonylmethoxy, carboxymethyl, methoxycarbonylmethyl, aminocarbonylmethoxy, aminocarbonylmethyl, N-phenylaminocarbonylmethoxy or N-phenylaminocarbonylmethyl, furthermore also acyl or benzoyl.
In particular, R2, R5 are H.
R3 is in particular, for example, H, COOA or xe2x80x94OCH2COOR6, where R6 is H or alkyl having 1-4 C atoms.
R6 is H, A or benzyl, but in particular H or alkyl having 1-4 C atoms.
X is preferably, for example, xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OOCxe2x80x94, xe2x80x94CONHxe2x80x94 or xe2x80x94NHCOxe2x80x94; xe2x80x94CH2Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94 is very particularly preferred.
Ar is preferably unsubstituted phenyl or naphthyl, furthermore phenyl or naphthyl, furthermore also biphenyl, which is preferably mono-, di- or trisubstituted, for example, by A, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, benzyloxy, phenethyloxy, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, phenylsulfinyl, phenylsulfonyl, nitro, amino, methylamino, ethylamino, dimethylamino, diethylamino, formamido, acetamido, propionylamino, butyrylamino, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, phenylsulfonamido, (4-methylphenyl)sulfonamido, carboxymethoxy, carboxyethoxy, methoxycarbonylmethoxy, methoxycarbonylethoxy, hydroxymethoxy, hydroxyethoxy, methoxyethoxy, carboxyl, methoxycarbonyl, ethoxycarbonyl, cyano, phenylaminocarbonyl, acyl or benzoyl.
Ar is therefore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tertbutylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p-(phenylsulfonamido)phenyl, o-, m- or p-(methylsulfonamido)phenyl, o-, m- or p-methylthiophenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.
Arxe2x80x2 is in particular, for example, phenyl or naphthyl, furthermore preferably, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, .o-, m- or p-carboxyphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-diethylamino)phenyl, 0-, m- or p-acetylphenyl, o-, m- or p-formylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl or o-, m- or p-methylsulfonylphenyl.
Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following subformulae Ia to Ii, which correspond to the formula I and in which the radicals not designated in greater detail have the meaning indicated in the formula I, but in which
in Ia R1, R4 in each case independently of one another are xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by OH, or are xe2x80x94COxe2x80x94Nxe2x95x90C(NH2)2;
in Ib R2, R5 are H;
in Ic R1, R4 in each case independently of one another are xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by OH, or are xe2x80x94COxe2x80x94Nxe2x95x90C(NH2)2,
R2, R5 are H and
R3 is H or COOR6;
in Id R1, R4 in each case independently of one another are xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by OH, or are xe2x80x94COxe2x80x94Nxe2x95x90C(NH2)2,
R2, R5 are H and
R3 is H, COOR6 or xe2x80x94Oxe2x80x94(CH2)COOR6;
in Ie X is xe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94;
in If R1, R4 in each case independently of one another are, xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by OH, or are xe2x80x94COxe2x80x94Nxe2x95x90C(NH2)2,
R2, R5 are H,
R3 is H or COOR6 and
X is xe2x80x94CH2xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CH2xe2x80x94;
in Ig R1, R4 in each case independently of one another are xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by OH, or are xe2x80x94COxe2x80x94Nxe2x95x90C(NH2)2,
R2, R5 are H,
R3, is H, COOR6 or xe2x80x94Oxe2x80x94(CH2)COOR6, and
X is xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94;
in Ih R1, R4 in each case independently of one another are xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by OH, or are xe2x80x94COxe2x80x94Nxe2x95x90C(NH2)2,
R2, R5 is H,
R3 is H, COOR6, xe2x80x94Oxe2x80x94CH2xe2x80x94COOR6, CH2xe2x80x94COOR6, xe2x80x94Oxe2x80x94CH2xe2x80x94CON(R6)2, CH2xe2x80x94CON(R6)2, xe2x80x94Oxe2x80x94CH2xe2x80x94CONHAr or CH2xe2x80x94CONHAr,
X is xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94,
R6 is H or A, and
A is alkyl having 1-4 C atoms;
in Ii R1, R4 in each case independently of one another are xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, which can also be monosubstituted by OH, or are xe2x80x94COxe2x80x94Nxe2x95x90C(NH2)2,
R2, R5 are H,
R3 is H, COOR6, xe2x80x94Oxe2x80x94(CH2)COOR6, CH2xe2x80x94COOR6, xe2x80x94Oxe2x80x94CH2xe2x80x94CON(R6)2, or CH2xe2x80x94CON(R6)2,
X is xe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94,
R6 is H or A, and
A is alkyl having 1-4 C atoms.
The compounds of the formula I and also the starting substances for their preparation are otherwise prepared by methods known per se, such as are described in the literature (e.g. in the standard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made in this case of variants which are known per se, but not mentioned here in greater detail.
If desired, the starting substance can also be formed in situ such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.
Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent.
Preferred starting substances for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but instead of one or more free amino and/or hydroxyl groups contain corresponding protected amino and/or hydroxyl groups, preferably those which instead of an H atom which is bonded to an N atom carry an amino protective group, in particular those which instead of an HN group carry an Rxe2x80x2xe2x80x94N group, in which Rxe2x80x2 is an amino protective group, and/or those which instead of the H atom of the hydroxyl group carry a hydroxyl protective group, e.g. those which correspond to the formula I, but instead of a group xe2x80x94COOH carry a group xe2x80x94COORxe2x80x3, in which Rxe2x80x3 is a hydroxyl protective group.
Preferred starting substances are also the oxadiazole derivatives which can be converted into the corresponding amidino compounds.
The introduction of the oxadiazole group is carried out, for example, by reaction of the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformic acid esters, N,Nxe2x80x2-carbonyldiimidazole or acetic anhydride.
It is also possible for a number ofxe2x80x94identical or differentxe2x80x94protected amino and/or hydroxyl groups to be present in the molecule of the starting substance. If the protective groups present are different from one another, in many cases they can be selectivly removed.
The expression xe2x80x9camino protective groupxe2x80x9d is generally known and relates to groups which are suitable for protecting (for blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. Typical groups of this type are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after, the desired reaction (or reaction sequence), their nature and size is otherwise not critical; however, those having 1-20, in particular 1-8, C atoms are preferred. The expression xe2x80x9cacyl groupxe2x80x9d is to be interpreted in the widest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxycarbonyl), 2-iodoethoxycarbonyl, aralkyloxycarbonyl such as CBZ (xe2x80x9ccarbobenzoxyxe2x80x9d), 4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.
The expression xe2x80x9chydroxyl protective groupxe2x80x9d is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other sites in the molecule. Typical groups of this type are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, furthermore also alkyl groups. The nature and size of the hydroxyl protective groups is not critical, since they are removed again after the desired chemical reaction or reaction sequence; groups having 1-20, in particular 1-10, C atoms are preferred. Examples of hydrokyl protective groups are, inter alia, benzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, benzyl and tert-butyl being particularly preferred.
The liberation of the compounds of the formula I from their functional derivatives is carried outxe2x80x94depending on the protective group usedxe2x80x94e.g. with strong acids, expediently with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic solvents, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, furthermore also alcohols such as methanol, ethanol or isopropanol, and also water.
Furthermore, mixtures of the abovementioned solvents are possible. TFA is preferably used in an excess without addition of a further solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are expediently between approximately 0 and approximately 50xc2x0; the reaction is preferably carried out between 15 and 30xc2x0 (room temperature).
The groups BOC, OBut and Mtr can preferably be removed, for example, using TFA in dichloromethane or using approximately 3 to 5N HCl in dioxane at 15-30xc2x0 C., the FMOC group using an approximately 5- to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30xc2x0.
Hydrogenolytically removable protective groups (e.g. CBZ, benzyl or the release of the amidino group from its oxadiazole derivative) can be removed, for example, by treating with hydrogen in the presence of a catalyst (e.g. of a noble metal, catalyst such as palladium, expediently on a support such as carbon, or such as moist Raney nickel with addition of, for example, acetic acid). Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the hydrogenolysis is carried out at temperatures between approximately 0 and 100xc2x0 and pressures between approximately 1 and 200 bar, preferably at 20-30xc2x0 and 1-10 bar. Hydrogenolysis of the CBZ group takes place well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30xc2x0.
Compounds of the formula I in which R1 and R4 are xe2x80x94C(xe2x95x90NH)xe2x80x94NH2 can preferably be obtained from the corresponding cyano compound.
The conversion of a cyano group into an amidino group is carried out by reaction with, for example, hydroxylamine and subsequent reduction of the N-hydroxyamidine using hydrogen in the presence of a catalyst such as, for example, Pd/C or Raney nickel. For the preparation of an amidine of the formula I (R1xe2x95x90xe2x80x94C(xe2x95x90NH)xe2x80x94NH2), ammonia can also be added to a nitrile of the formula I (R1=CN). The addition is preferably carried out in a number of stages by, in a manner known per se
a) converting the nitrile using H2S into a thioamide, which is converted using an alkylating agent, e.g. CH3I, into the corresponding S-alkylimidothio ester, which for its part reacts with NH3 to give the amidine,
b) converting the nitrile using an alcohol, e.g. ethanol in the presence of HCl, into the corresponding imido ester and treating this with ammonia, or
c) reacting the nitrile with lithium bis-(trimethylsilyl)amide and then-hydrolysing the product.
Preparation of the cyano compound is carried out according to methods known per se.
Compounds of the formula I in which R1 and R4 are xe2x80x94CON(xe2x95x90NH)xe2x80x94NH2 can preferably be obtained from the corresponding alkoxycarbonyl compounds by reacting with guanidine.
It is furthermore possible to convert a compound of the formula I into another compound of the formula I by converting one or more radical(s) R1, R21 R3, R4 and/or R5 into one or more radical(s) R1, R2, R3, R4 and/or R5, e.g. by acylating an amino group or reducing nitro groups (for example by hydrogenation on Raney nickel or Pd-carbon in an inert solvent such as methanol or ethanol) to amino groups.
Esters can be hydrolysed, for example, using acetic acid or using NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100xc2x0.
Furthermore, free amino groups can be acylated in a customary manner using an acidchloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, expediently in an inert solvent such as dichloromethane or TIF and/or in the presence of a base such as triethylamine or pyridine at temperatures between xe2x88x9260 and +30xc2x0.
As a rule, the reaction is carried out in an inert solvent, in the presence of an acid-binding agent, preferably of an alkali metal or alkaline earth metal if hydroxide, carbonate or bicarbonate or of another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or caesium. The addition of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline or of an excess of the amino components of the formula II or of the alkylation derivative of the formula III may also be favourable. Depending on the conditions used, the reaction time, is between a few minutes and 14 days, the reaction temperature being between approximately 0xc2x0 and 150xc2x0, normally between 20xc2x0 and 130xc2x0.
Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitrites such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitrbmethane or nitrobenzene; esters such as ethyl acetate or mixtures of the solvents mentioned.
A base of the formula I can be converted with an acid into the associated acid addition salt, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. Possible acids for this reaction are those which yield physiologically acceptable salts. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids, laurylsulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
On the other hand, compounds of the formula I can be converted using bases (e.g. sodium or potassium hydroxide or sodium or potassium carbonate) into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts or into the corresponding ammonium salts. Physiologically acceptable organic bases, such as, for example, ethanolamine, can also be used.
The invention furthermore relates to the use of the compounds of the formula I and/or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular in a non-chemical way. In this context, they can be brought into a suitable dose form together with at least one solid, liquid and/or semi-liquid excipient or auxiliary and, if appropriate, in combination with one or more further active compounds.
The invention furthermore relates to pharmaceutical preparations, comprising at least one compound of the formula I and/or one of its physiologically acceptable salts.
These preparations can be used as medicaments in human or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. In particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations.
The preparations indicated can be sterilized and/or can contain auxiliaries such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more further active compounds, e.g. one or more vitamins.
The compounds of the formula I and their physiologically acceptable salt can be used an the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
In this connection, as a rule the substances according to the invention are preferably administered in doses of between approximately 1 and 500 mg, in particular between 5 and 100 mg per dose unit. The daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight. The specficdose for each patient depends, however, on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
Above and below, all temperatures are indicated in xc2x0 C. In the following examples, xe2x80x9ccustomary working upxe2x80x9d means: if necessary, water is added, if necessary, depending on the constitution of the final product, the mixture is adjusted to a pH of between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel and/or by crystallization.
Mass spectrometry (MS): EI (electron impact ionization) M+; FAB (fast atom bomardment) (M+H)+.